Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K+ in rat hippocampus.

Spreading depression (SD) is known to be involved in the N-methyl-D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K+ perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 microM) and nitrobenzylthioinosine (NBI) (50 microM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEg and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR+NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR+NBI were blocked by application of a selective antagonist of adenosine A1 receptor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the A1 receptor in rat hippocampus.